A major hallmark of Alzheimer's disease (AD) is the accumulation of neurotoxic p-amyloid (A(3) peptide in the[unreadable] brain. Inappropriate oligomerization of Ap peptides into soluble high molecular weight (HMW) species and[unreadable] the eventual deposition of A(3 peptides into extracellular A(3 plaques in the brain are major events involved in[unreadable] AD neuropathology and associated dementia. Accumulating evidence indicates a central role for soluble A|3[unreadable] oligomers (with molecular weight higher than tetramers but lower than decamers) in preclinical AD cognitive[unreadable] deterioration as well as in AD dementia. The overall goal of the proposed studies in Project 3 is to identify[unreadable] bioactive grape seed extract (GSE)- polyphenolic compounds that can prevent AD-type amyloid[unreadable] neuropathology and cognitive deterioration in the Tg2576 mouse model of AD. The proposed studies are[unreadable] supported by preliminary evidence showing that a commercially available GSE (herein defined as NS-MA2[unreadable] GSE) containing a variety of polyphenolic compounds, prevents the oligomerization of Ap peptides into[unreadable] soluble-extracellular HMW species and eventually AD - type Ap neuropathology, coincidental with the[unreadable] attenuation of spatial reference memory impairment in Tg2576 mice. Based on this consideration, the[unreadable] proposed studies are specifically designed to further identify and document how NS-MA2 GSE polyphenolic[unreadable] compounds are absorbed, metabolized and ultimately prevent AD-type cognitive deterioration in Tg2576[unreadable] mice. The proposed studies will be the first to systematically identify GSE polyphenolic compounds in vivo[unreadable] using a combination of LC-tandem mass spectrorhetry and NMR techniques. Furthermore, this approach will[unreadable] make use of 14C labeled grape fractions and Accelerator Mass Spectrometry to accurately determine the[unreadable] pharmacokinetics of NS-MA2 GSE polyphenolic compounds in plasma and in the brain. Data from the[unreadable] proposed studies will provide impetus for immediate application to prevention of cognitive deterioration in[unreadable] AD, and potentially also in mild cognitive impairment (MCI), whose subjects are at high risk of developing AD[unreadable] dementia.[unreadable]